Coronary atherosclerosis is a major cause of death in women in the USA. Although coronary artery bypass surgery decreases symptomatic and clinical evidence of ischemia, it does not alter the underlying process. Patients may present several years later with recurrent symptoms that may be a result of occlusion of saphenous vein grafts, development of atherosclerotic disease in the vein grafts, or progression of underlying disease. Any intervention that can reduce the rate of progression of coronary atherosclerosis following bypass surgery would provide significant benefit for women following bypass surgery and possibly for other women with atherosclerotic disease. Observational studies suggest that postmenopausal estrogen replacement therapy is associated with a reduction in cardiac morbidity. However the benefit for hormone replacement therapy in women with established coronary disease has not been demonstrated. This randomized, double-blind controlled trial tests the hypothesis that postmenopausal hormone replacement therapy in women following coronary bypass surgery will reduce the occurrence of graft occlusion and delay the development of graft atherosclerosis. Women will be randomized to esnadiol with daily medroxyprogesterone or placebo within 4 weeks of bypass surgery. Graft occlusion and development of vein graft atherosclerosis will be measured by comparing quantitative coronary angiographic and intravascular ultrasonographic assessment of disease severity and extent performed at 6 months and 3.5 years after randomization. The primary outcome variables will be the occurrence of graft occlusion at 6 months and the change in severity and extent of atherosclerosis in the saphenous vein grafts over 3 years. The proposal will determine th influence of hormone replacement therapy on the primary outcome variables. The pathophysiologic mechanisms of interest in this proposal are platelet activation, fibrinogen binding to platelets, vascular reactivity, coagulation and fibrinolytic factors and lipoprotein composition. The proposal will test the hypothesis that these variables predict the occurrence of graft occlusion and rate o development of graft atherosclerosis. The proposal also tests the hypothesis that hormone replacement therapy exerts its beneficial effects by its effects on those risk factors in addition to more traditional risk factors including the lipids and lipoprotein profile.